Clinical and economic impact of long-acting injectable antipsychotics in patients previously treated with short-acting oral antipsychotics

BACKGROUND: Available literature supports the use of long-acting injectable (LAI) antipsychotics over short-acting oral (SAO) formulations. The majority of evidence is centered on patients with schizophrenia insured under the Medicaid benefit. OBJECTIVE: To assess real-world clinical and economic outcomes of LAI compared with SAO antipsychotics in patients with psychiatric conditions insured under commercial, health care exchange, or Medicare plans. METHODS: In this exploratory treatmenteffectiveness study, a retrospective, before and after study design was used to evaluate differences in clinical and economic outcomes in patients switching from SAO to LAI antipsychotics. Patients who had at least 1 claim for an LAI antipsychotic and a psychiatric diagnosis were considered eligible for the study if they were continuously enrolled in a commercial, health care exchange, or Medicare plan for 12 months before (preperiod) and 12 months after (postperiod) their first LAI antipsychotic claim. During the preperiod, patients were required to have filled at least a 30-day supply of any SAO antipsychotic medication. Clinical outcomes included health care resource utilization (eg, hospitalizations per member per year [PMPY]), adherence measures, and medication switch trends. Economic outcomes included total per member per month (PMPM) spending across the medical benefit alone, the pharmacy benefit alone, and the combined spending across both benefits. Additionally, we examined patient costs and health plan spending within each of these categories. RESULTS: There was a significant decrease in overall hospitalizations PMPY (1.80 vs 0.88; P < 0.001) and psychiatric hospitalizations PMPY (0.65 vs 0.20; P <0.001) when comparing patients treated with SAO antipsychotics in the preperiod to the same patients treated with LAI antipsychotics in the postperiod, respectively. No differences were observed in the percentage of days covered with SAO and LAI agents (87.4% vs 85.8%; P=0.312). More patients switched between SAO antipsychotics during the preperiod, as compared with the number who switched between LAI antipsychotics during the postperiod (57.4% vs 10.3%; P < 0.001). On average, patients switched medications sooner in the preperiod vs the postperiod (114.50 vs 211.26 days; P < 0.001). No difference was observed between the preperiod and postperiod in total spending PMPM ($3,798.76 vs $3,702.63; P = 0.826) CONCLUSIONS: Patients switching from SAO to LAI antipsychotics experienced fewer hospitalizations, with no change in overall spending. Adherence was similar, though fewer medication switches occurred and there was a longer time before switching medications with LAI compared with SAO antipsychotics


METHODS:
In this exploratory treatmenteffectiveness study, a retrospective, before and after study design was used to evaluate differences in clinical and economic outcomes in patients switching from SAO to LAI antipsychotics. Patients who had at least 1 claim for an LAI antipsychotic and a psychiatric diagnosis were considered eligible for the study if they were continuously enrolled in a commercial, health care exchange, or Medicare plan for 12 months before (preperiod) and 12 months after (postperiod) their first LAI antipsychotic claim. During the preperiod, patients were required to have filled at least a 30-day supply of any SAO antipsychotic medication. Clinical outcomes included health care resource utilization (eg, hospitalizations per member per year [PMPY]), adherence measures, and medication switch trends. Economic outcomes included total per member per month (PMPM) spending across the medical benefit alone, the pharmacy benefit alone, and the combined spending across both benefits. Additionally, we examined patient costs and health plan spending within each of these categories.

RESULTS:
There was a significant decrease in overall hospitalizations PMPY (1.80 vs 0.88; P < 0.001) and psychiatric hospitalizations PMPY (0.65 vs 0.20; P < 0.001) when comparing patients treated with SAO antipsychotics in the preperiod to the same patients treated with LAI antipsychotics in the postperiod, respectively. No differences were observed in the percentage of days covered with SAO and LAI agents (87.4% vs 85.8%; P = 0.312). More patients switched between SAO antipsychotics during the preperiod, as compared with the number who switched between LAI antipsychotics during the postperiod (57.4% vs 10.3%; P < 0.001). On average, patients switched medications sooner in the preperiod vs the postperiod (114.50 vs 211.26 days; P < 0.001). No difference was observed between the preperiod and postperiod in total spending PMPM ($3,798.76 vs $3,702.63; P = 0.826).

Plain language summary
Antipsychotic medications can help different psychiatric diseases. They can be given by mouth once or twice daily or as injections given by health care providers every 2 weeks up to every 6 months. This study aimed to find out if using the injections was better for patients compared with using the oral versions. Using injections made it less likely that patients would go to the hospital and did not lead to higher costs.

Implications for managed care pharmacy
In commercial-, health care exchange-, and Medicare-insured patients treated with long-acting injectable (LAI) antipsychotics who were previously treated with short-acting oral antipsychotics, LAI formulations led to fewer hospitalizations and no change in overall spending. Spending on the pharmacy benefit increased, potentially impacting payer willingness to cover LAI antipsychotics if they only offer pharmacy coverage. Payers may use this information to refine benefit design strategies of LAI antipsychotics (eg, formulary coverage, use of prior authorization).
Schizophrenia and bipolar disorder represent 2 of the most recognizable psychiatric conditions. Though they affect only a small proportion of the population, the economic impact of schizophrenia and bipolar disorder are significant, with an estimated annual economic burden of $155 billion for schizophrenia in 2013 and approximately $200 billion for bipolar I disorder in 2015. [1][2][3] Approximately 25% of spending for these conditions is related to direct costs, including medications. [1][2] Antipsychotic medications are a critical component of the overall management of these psychiatric disorders. 4,5 A number of short-acting oral (SAO) and long-acting injectable (LAI) antipsychotic formulations are commercially available, and guidelines emphasize the role of patientspecific factors in the medication selection process. 4 One important factor in medication selection is the treatment burden associated with each given therapy. Although the LAI antipsychotics require administration by a health care provider, they are dosed significantly less often (as infrequently as once every 6 months) compared with SAO antipsychotics, which are self-administered and typically dosed once daily. 4,6 The extended dosing interval of LAI antipsychotics has the potential to reduce medication burden, which can positively influence patient outcomes. 4 The majority of previous before and after studies have demonstrated improved clinical outcomes, neutral or positive economic trends, and improved adherence. [7][8][9] Despite these trends, design limitations within these studies may reduce the applicability of these data to real-world patient populations. Existing research varies by plan type (eg, commercial, Medicare, etc) and specific antipsychotic medications included, outcomes evaluated, and psychiatric conditions studied. The bulk of available research focuses on Medicaid patients or those treated within the Veterans Affairs system. 7,10-12 Additionally, there is great variety between the antipsychotics included in each study and limited studies are available that evaluate both economic and clinical outcomes within the same patient population. Finally, previous studies have a heavy focus on schizophrenia patients, with limited data regarding other psychiatric conditions. [7][8][9][10][11][12] To address these gaps in research, we evaluated the impact of switching from SAO to LAI antipsychotic medications in a broad population.

Methods
We developed a retrospective, before and after study comparing SAO and LAI antipsychotics using medical and pharmacy claims data for Highmark Inc. members. Highmark Inc. is a national health insurance organization, which covered approximately 6 million lives under commercial, health care exchange (subsequently referred to as "exchange"), and Medicare plans at the time of this analysis. Prior to the start of the study, approval was received by the Wilkes University Institutional Review Board.
Individuals were included in this study if they received medical and pharmacy coverage under a Highmark Inc. commercial, exchange, or Medicare plan during the study period (January 1, 2017, to June 1, 2021) and had at least 1 claim for an LAI antipsychotic (Supplementary Table 1, available in online article) and a diagnosis for a psychiatricrelated condition. To determine the eligibility based on diagnosis, a full list of International Classification of Diseases, Tenth Revision (ICD-10) diagnosis codes for all patients who had filled an LAI antipsychotic were retrieved. Each code was assessed to determine its relevance to the analysis. The full list of ICD-10 diagnosis codes included in the study are available in Supplementary Table 2.
The index date was individualized for each member and was defined as the date of each patient's first LAI antipsychotic claim ( Figure 1). Members were required to be continuously enrolled for 12 months before the index date ("preperiod") to 12 months after ("postperiod"). During the preperiod, patients were required to have filled at least a 30-day supply of any SAO antipsychotic medication (Supplementary Table 3).
All patients initiating LAI antipsychotics are recommended to be started on an SAO formulation to ensure tolerability. Each medication has a different initiation strategy and an appropriate number of days of overlap between the SAO and LAI formulations. 4 Patients were excluded from the study if the number of days of SAO antipsychotic overlap was greater than the amount suggested within the medication's US Food and Drug Administration-approved labeling (Supplementary Table 1). Patients were also excluded if they were not continuously enrolled within one plan type or if they passed away during the study period.
To directly compare the effects of a medication switch from SAO to LAI formulations, we evaluated the difference in individual patient outcomes between the preperiod and the postperiod. Results were grouped into 2 categories. CONCLUSIONS: Patients switching from SAO to LAI antipsychotics experienced fewer hospitalizations, with no change in overall spending. Adherence was similar, though fewer medication switches occurred and there was a longer time before switching medications with LAI compared with SAO antipsychotics. the total days a member was supplied with medication by the total days in the period and presenting the value between 0% and 100%. The total number of days in the preperiod was the difference between the index date and the date of the first SAO antipsychotic claim. The total number of days in the postperiod was 365 for all patients, calculated as 12 months after the index date.
All analyses were conducted in the statistical computing language R, version 4.0.0. Statistical significance was defined as P < 0.05.

Results
A total of 238 members met the inclusion criteria for this analysis ( Figure 2). The population had a mean age of 50.9 years (SD ± 20.4) at the index date and 51.8% were male. Most patients were enrolled in commercial plans (51.2%), followed by Medicare (45.6%) and exchange plans (3.2%). In the preperiod, 34.6% and 93.3% of patients had at least 1 claim for first-and second-generation SAO antipsychotics, respectively. In the postperiod, 37.5% of patients had at least 1 claim for first-generation and 66.2% for second-generation LAI antipsychotics. Although all patients included in the study were required to have a psychiatric diagnosis, Clinical outcomes included health care resource utilization (eg, hospitalizations per member per year [PMPY]), adherence measures, and medication switch trends. Economic outcomes included total per member per month (PMPM) spending across the medical benefit alone, the pharmacy benefit alone, and the combined spending across both benefits. Additionally, we examined patient costs and health plan spending within each of these categories.

STATISTICS
Descriptive statistics, including means and 95% CIs for continuous variables and frequency percentages for categorical variables, are presented in Table 1, Table 2, and  Table 3. Continuous variables were compared between the preperiod and postperiod using either paired t-tests for parametric data or Wilcoxon signed-rank tests for nonparametric variables. For proportions data, such as the percentage of members meeting adherence criteria, two proportion Z-tests were used to establish significance. Lastly, Poisson regression was used to compare all preperiod and postperiod count data, in which any number of events PMPY were analyzed.
Adherence calculations were completed using the percentage of days covered (PDC), which was calculated using available claims data. The PDC was determined by dividing   Table 2). We observed a significantly lower average number of days covered with SAO antipsychotics in the preperiod, as compared with the average number of days covered with LAI antipsychotics in the postperiod (212.31 vs 248.5 days; P = 0.002). There were no differences observed in adherence to SAO and LAI agents based on either the PDC (87.4% vs treated with SAO antipsychotics in the preperiod to the same patients treated with LAI antipsychotics in the postperiod, respectively. Specifically, schizophrenia-related hospitalizations PMPY (0.25 vs 0.16; P = 0.048) and hospitalizations for other nonschizophrenia psychiatric complications PMPY (0.57 vs 0.27; P < 0.001) both decreased from the preperiod to the postperiod, respectively. The number of overall outpatient health care provider visits PMPY increased from the preperiod to the postperiod (9.03 vs 46.7% of members had a schizophrenia-related diagnosis code and 37.6% had a bipolar-related diagnosis code; the remaining 21.7% of members had another psychiatric diagnosis not classified as schizophrenia or bipolar disorder (Table 1).

Discussion
Our study found that patients initially treated with an SAO antipsychotic who were subsequently switched to an LAI antipsychotic experienced an improvement in various clinical outcomes despite no significant change in total spending, total patient spending, or total health plan spending on a PMPM basis. In our analysis, an increase in outpatient health care provider visits was seen after patients were switched to LAI antipsychotics. This finding was anticipated and is likely due in part to the requirement for LAI antipsychotics to be administered by a health care professional, thereby necessitating more frequent provider visits. Notably, there was no change in the number of psychiatric specialist visits between groups. There may have simply been no change in the frequency of specialist visits during the preperiod and postperiod, but less frequent follow-up due to improved disease control may have been balanced by more frequent visits for medication administration.
Other measures of health care resource utilization, including overall hospitalizations PMPY, psychiatric hospitalizations PMPY, hospitalizations for a schizophrenia-related diagnosis PMPY, and hospitalizations for other nonschizophrenia-related psychiatric complications PMPY were significantly reduced with LAI antipsychotics compared with SAO antipsychotics.
One possible reason for the improvement in outcomes was a greater number of days covered by antipsychotic medication in the postperiod. Our study enrolled patients who had at least 30 days of SAO antipsychotic medication filled in the preperiod and at least 1 claim for an LAI antipsychotic. We then investigated the clinical differences 12 months before and 12 months after patient spending PMPM ($230.38 vs $217.97; P = 0.632) and total health plan spending PMPM ($3,103.80 vs $3,105.04; P = 0.997) did not change significantly (Table 3).
During the preperiod, a greater number of patients switched between SAO antipsychotics, as compared with the number of patients who switched between LAI antipsychotics during the postperiod (57.4% vs 10.3%; P < 0.001). Of the members who switched between SAO antipsychotics in the preperiod compared with those who switched between LAI antipsychotics in the postperiod, the average number of days before a switch was significantly lower with SAO antipsychotics (114.50 vs 211.26 days; P < 0.001) ( Table 2).

ECONOMIC OUTCOMES
There was no statistically significant difference observed between the preperiod and postperiod in total spending PMPM ($3,798.76 vs $3,702.63; P = 0.826). Similarly, total

TABLE 3
Economic Outcomes preperiod findings and suggest benefit of LAI antipsychotic therapy over SAO therapy, when the benefit of LAI antipsychotic medications was in fact greater than no therapy for the majority of the preperiod; however, our intention was to capture real-world medication use patterns to understand the clinical and economic benefits in patients who were switched to LAI antipsychotic medications after at least 30 days of SAO antipsychotic therapy. Additionally, the mean number of days covered in the preperiod was 212 (median = 213.5), thereby alleviating concern that a significant number of patients received only a small amount of SAO antipsychotic therapy prior to transitioning to an LAI formulation. Contrary to existing evidence and suggested benefit conveyed by the guidelines, no differences in adherence were noted between SAO and LAI antipsychotics. We noted high adherence in both groups compared with what has been previously reported in the literature. This may be due in part to behavioral health initiatives at Highmark Inc. Although no differences in PDC or proportion of members achieving at least an 80% PDC were noted, we identified that fewer members treated with LAI antipsychotics required a switch to an alternative LAI medication and, on average, were treated for a longer period of time before switching.
In addition to the clinical benefits of LAI antipsychotics shown in this study, overall spending did not change significantly between the preperiod and postperiod. The components of overall spending (ie, medical and pharmacy spending) did change significantly between periods. Medical spending was significantly greater during the preperiod, whereas pharmacy spending was significantly greater during the postperiod. There are several possible explanations for these findings. First, it is possible that the economic impact of the clinical benefits of LAI antipsychotics found in this study (eg, fewer hospitalizations, fewer provider visits, etc) outweighed the cost of the medications. That is, when patients were treated with LAI antipsychotics, they used fewer health care services on the medical benefit. In turn, this ultimately led to significantly lower overall spending compared with when those same patients received SAO antipsychotics.
Another consideration is that LAI antipsychotics are to be administered by a health care professional and therefore are commonly covered under the medical benefit for commercial and exchange plans. On the other hand, Medicare allows these agents to be covered under either the medical (Part B) or pharmacy (Part D) benefits. Given the widespread availability of generic, low-cost SAO antipsychotics and the significant cost of most LAI antipsychotics, it is possible that a few LAI antipsychotic claims on the pharmacy benefit had a greater impact on spending than LAI antipsychotic the first LAI antipsychotic fill. We found a significantly greater number of days covered in the postperiod, as compared with the preperiod, meaning that patients received more medication, on average, in the postperiod.
It is somewhat counterintuitive that SAO antipsychotics may lead to a greater number of days covered than LAI formulations. This may occur though, as claims for these agents may be billed for up to a 90-day supply, whereas most LAI antipsychotic claims cover no more than 30 days; however, we saw the opposite, which we believe may be due in part to our study design. Our study may have captured patients who were "new starts" on SAO antipsychotic medications who were transitioned to LAI antipsychotic therapy after a short time (eg, after a single 1-month claim for an SAO medication). This could confound the 12-month All patients enrolled in a Highmark Inc. insurance plan n = 10,531,719 All patients with Highmark Inc. pharmacy and medical insurance n = 4,980,410 Patients with ≥ 1 fill of an LAI antipsychotic and ≥ 1 medical claim for a psychiatric diagnosis n = 1,746 Patients continuously enrolled within 1 plan type (eg, commercial, Medicare, etc) from 12 months prior and 12 months after their first LAI antipsychotic claim n = 1,076 Patients with ≥ 30 days' worth of claims for SAO antipsychotic medication(s) within the 12 months before the first LAI antipsychotic claim n = 346 Patients not exceeding the number of days of SAO and LAI antipsychotic overlap suggested by FDA labeling n = 238 FDA = US Food and Drug Administration; LAI = long-acting injectable; SAO = short-acting oral.

FIGURE 2 Patient Selection Process for Study Analysis
for the general population were influenced by any given subgroup. Finally, future studies may be conducted to determine whether coverage of an LAI antipsychotic medication under a particular benefit (ie, medical vs pharmacy) impacts spending or if the concomitant use of other psychotropic medications impacts outcomes in any meaningful way.

Conclusions
Patients switching from SAO to LAI antipsychotics experienced fewer hospitalizations, with no change in overall spending. Adherence was similar, though fewer medication switches occurred and there was a longer time before switching medications with LAI compared with SAO antipsychotics.

DISCLOSURES
Funding for this study was provided by Highmark Inc., but the sponsor had no role in the study outside the final review of the submitted manuscript.